Design and Evaluation of Curcumin-Derived Aldopentose Compounds: Unlocking their Antidiabetic Potential through Integrative In Vitro, In Vivo, and In Silico Studies on Carbohydrate-Degrading Enzymes.

Abstract

Natural polyphenol compounds such as curcumin can inhibit carbohydrate-hydrolyzing enzymes, which may offer an alternative to expensive and potentially side-effect-inducing α-glucosidase inhibitors like acarbose. Hence, this study carried out the synthesis of curcumin aldopentose derivatives, examining their capacity to inhibit the α-glucosidase and α-amylase enzymes with the aim to alleviate hyperglycemia. Initially, the aldopentose derivatives from curcumin were synthesized and confirmed by spectroscopic methods such as MS, ¹³CNMR, ¹HNMR, and FTIR. Afterward, we investigated the inhibitory effects of all derivatives on the α-amylase and α-glucosidase enzymes spectroscopically and determined their inhibition mechanism. We assessed the antioxidant activity and the stability of the synthetic derivatives in the simulated intestinal environment. Finally, we measured the postprandial blood glucose level after administering saturated starch in vivo. The modified compounds showed improved inhibitory effects compared to curcumin alone, with compound C3 demonstrating particularly strong enzyme inhibition. However, when compared with acarbose, a known commercial antidiabetic drug, the synthetic compounds showed lower inhibitory activity against both enzymes, resulting in fewer side effects related to undigested polysaccharides in the gut. Molecular docking studies show introducing a pentose moiety to the curcumin backbone enhanced docking affinities toward both enzymes and subsequently altered the associated IC₅₀ and K_i values. Overall, compound C3 has the potential to be an inhibitor of carbohydrate-degrading enzymes and can effectively reduce glucose absorption in vivo. Given its antioxidant capabilities and reasonable stability, the compound in question shows promises as a potent derivative for the development of new anti-hyperglycemic drugs in future research endeavours.